Certain pyridylalkyl derivatives of 2-amino-5-phenyl-2-oxazolin-4-ones

ABSTRACT

2-Pyridylalkylamino-5-phenyl-2-oxazolin-4-ones with optional simple substituents in the phenyl ring or in the connecting alkylamino bridge between the two heterocyclic rings were found to be valuable anti-depressants when administered orally to warmblooded animals.

United States Patent Lee [451 Aug. 1, 1972 [54] CERTAIN PYRIDYLALKYL [5 6] References Cited DERIVATIVES OF Z-AMINO-S- OTHER PUBLICATIONS PHENYL-2-OXAZOLIN-4-ONES Inventor: Cheuk Man Lee, Waukegan, lll.

Assignees Abbott Laboratories, North Chicago, Ill.

Filed: Sept. 25, 1970 Appl. No.: 75,679

US. Cl ..260/295 AM, 260/295.5 A, 424/266 Int. Cl. ..C07d 31/44 Field of Search ..260/295 AM, 295.5 A

Chem. Abstracts, Vol. 57, 13, 760-i-l3, 76l-c, (1962) abstracting Belgian Patent No. 613,985 dated Feb. 28, 1962 Primary ExaminerAlan L. Rotman Att0meyRobert L. Niblack ABSTRACT 1 1 Claims, No Drawings 1 2 CERTAIN PYRIDYLALKYL DERIVATIVES OF 2- 2 1 2 E g g g 173-4 DETAILED DESCRIPTION OF I HE IN VENTION 3 t: 1v}; 1: 4 199-200 2 133-4 The present invention is directed to new chemical 5 H H l H 4 173-5 compounds as well as their use as tranquilizers and 13 3 i S i at? anti-depressants. More particularly, the mventron 1s B 345 g 1 21 g 17 P 14 directed to compounds of the formula 15 m H 1 Ph 2 12m 16 1-1 Me 1 11 2 144-5 H I 10 17 11 1-1 1 Me 2 134-5 T Q 1 1' TIP-C H (C H2) "If I Me indicates methyl and Ph stands for phenyl. X l

. a .2 l5 EXAMPLE18 wherein X s hydrogen halogen, trifluoromethyl or A mixture Of g. Of 2-antin05-phenyl-2-0xaz0lin- 4-one and 36.6 g. of 2-(methylaminomethyl)pyridine methoxy, m is 0 or 1, R is hydrogen or methyl, R 1s hydrogen or methyl and is hydrogen, methyl or was stirred and heated in an 011 bath ma ntamed at phenyl. These new compounds have a very interesting IMP-50M for 4 l t excess was then pharmacological profile: they are classified as tranqum 20 removed by vacuum drstrllanon and the resldue was izers with pronounced anti-depressant activity and exg lfi ai P 'g of pure tremely low toxicity. Unlike other tranquilizers, the 3.3 1 gi g gP p enyfixnew compounds have no sedative effect which distinazo m me mg at guishes them very favorably over other tranquilizers EXAMPLE 19 and chemically closely related 5-phenyl-4-oxazolinones In a repetition of Example 18 but replacing the above The new compounds are enerall prepared b jz(methylmn omethyl)pyndme with the correspfmd' refluxing 2-amino-5-phenyl-2-(xazolin 4-ones witha t mg 4'subsmutFd compound least one molar equivalent of the appropriate ar'ninoalh l z Y kylpyridine for at least 2 days, using an inert organic meltmg at 186 was obtamedsolvent as the reaction medium which has a boiling point below 120 C. Altemately, i.e., when R is methyl, LE 20 2-amino-5-phenyl-2-oxazolin-4-one is heated with exa further l'ePetltlon of f f p but reRlacmg cess methylaminoalkylpyridine to 125-150 c. for at the y ybpy with an eqwmolar least 2 h amount of 2-(methylaminoethyl)pyridine, pure 2-[(2- ln order to illustrate the above general procedure y y E y lg g l f y more specifically, reference is made to the following one meltmg at 130 was Obtainedexamples WhlCh, however, are not meant to l1m1t the EXAMPLEZI present invention in any respect.

, The anti-depressant activity of the compounds EXAMPLE 1 described above was tested in mice by the modified A mixture of 8.8 g. of 2-amino-5-phenyl-2-oxazolin- W- E (described y Everett in Excerptla 4-one, 5.4 g. of 2-aminomethylpyridine and 300 ml. of gress sFnes P 164T7) The test ammals absolute ethanol was refluxed under stirring for 96 were g ven a 2 percent suspension of the test comhours. The solvent was then evaporated in vacuo and Pound Percent 8 the oral the residue was recrystallized from ethanol to give 7.3 P F 4 w mung s cale of 1 g of-pure 2 [(2 pyridy1methyl)amim] 5 phenyl indicating shght actlvlty, 2 representing moderate and 1, 0 c. 3 indicating pronounced activity. The test compounds azolm 4 meltmg at 9 are identified in the following table by reference to the EXAMPLES 2-17 above example numbers. The table also lists the oral LD values for mice indicating the extremely low tox The procedure of Example 1 was followed in each of icities ofthe new compounds the following examples wherein in each case,

equimolar amounts of 2-amino-5-phenyl-2-oxazolin-4- TABLE] one or the correspondingly S-disubstituted derivatives thereof (Examples 6, l4, l5 and 17) are refluxed with g who DSa8e $352) the corresponding aminoalkylpyridine. The following table lists the melting points of the specific compounds 1 1.0 so 2 together w1th the subst1tuents as designated in formula l m 5:: 100 my 3 l as well as the position of the pyridine ring (Py-Pos.) to g 1.8 g/kg Ing/kg which the alkylene groups is attached. In all instances, 8 1:0 $5 100 2%: 2 R is hydrogen. 9 1.0 g/kg 100 mg/kg 2 12 1.0 g/kg 25 mg/kg 3 14 L0 g/kg 25 mg/kg 3 Ex. 15 1.0 g/kg 2s mglkg 3 No. X R m R" Py-Pos mp. C 16 1.0 glkg 25 mg/kg 1 17 0.7 g/kg 25 mg/kg 3 166 7 18 Log/kg mg/kg 2 2 H H 0 H 3 19 1.0 25 k 1 3 11 11 o 11 4 148-50 81kg g As seen above, the oral toxicity values are so low that in most instances, a LD cannot even be established within practical dosage limits. In view of the low doses required to exhibit moderate to pronounced antidepressant activity, it is clearly demonstrated that the new compounds have excellent therapeutic indexes.

Although the above activity table lists the ratings of the bases according to formula i, it is to be understood that the new compounds may also be administered in form of their non-toxic acid addition salts, particularly the hydrochloride, sulfate, phosphate, acetate, citrate, succinate or tartrate salts. The bases or the corresponding salts may conveniently be formulated into practical solid dosage forms for oral administration, i.e., tablets, pills, lozenges, wafers or into liquid preparations such as a syrup or similar fluids. For any of these dosages forms, the usual pharmaceutically acceptable excipients may be used such as fillers, flavoring agents, coloring agents or the above compounds or their nontoxic salts may be combined with other pharmaceutically active ingredients to make preparations with dual or synergistic effects.

I claim:

1. A compound of the formula 4 wherein X is hydrogen, halogen, trifluoromethyl or methoxy, m is 0 or 1, R is hydrogen or methyl, R is hydrogen or methyl and R is hydrogen, methyl or phenyl.

2. The compound of claim 1 wherein R, R, R" and X. are hydrogen and the pyridine ring is attached at the 2-position.

3. The compound of claim 2 wherein m is 0.

4. The compound of claim 2 wherein m is l.

5. The compound of claim 1 wherein R, R, and R" are hydrogen, m is 1, X is the methoxy group in the 4- position, and the pyridine ring is a attached at the 2- position.

6. The compound of claim 1 wherein R, R and X are hydrogen and R" is phenyl and the pyridine ring is attached at the 2-position.

7. The compound of claim 6 wherein m is O.

8. The compound of claim 6 wherein m is l.

9. The compound of claim 1 wherein R, R and X are hydrogen, R" is methyl, m is 1 and the pyridine ring is attached at the 2-position.

10. The compound of claim 1 wherein R and R are hydrogen, X is chlorine in the 4-position of the phenyl ring, R" is phenyl, m is 1 and the pyridine ring is attached at the 2-position.

11. The compound of claim I wherein R is methyl, R', R" and X are hydrogen, m is 0 and the pyridine ring is attached at the 2-position. 

2. The compound of claim 1 wherein R, R'', R'''' and X are hydrogen and the pyridine ring is attached at the 2-position.
 3. The compound of claim 2 wherein m is
 0. 4. The compound of claim 2 wherein m is
 1. 5. The compound of claim 1 wherein R, R'', and R'''' are hydrogen, m is 1, X is the methoxy group in the 4-position, and the pyridine ring is a attached at the 2- position.
 6. The compound of claim 1 wherein R, R'' and X are hydrogen and R'''' is phenyl and the pyridine ring is attached at the 2-position.
 7. The compound of claim 6 wherein m is
 0. 8. The compound of claim 6 wherein m is
 1. 9. The compound of claim 1 wherein R, R'' and X are hydrogen, R'''' is methyl, m is 1 and the pyridine ring is attached at the 2-position.
 10. The compound of claim 1 wherein R and R'' are hydrogen, X is chlorine in the 4-position of the phenyl ring, R'''' is phenyl, m is 1 and the pyridine ring is attached at the 2-position.
 11. The compound of claim 1 wherein R is methyl, R'', R'''' and X are hydrogen, m is 0 and the pyridine ring is attached at the 2-position. 